This is the final resubmission of an RO1 application from a new investigator aimed at defining novel mechanisms of HIV-1-induced dysfunction of natural killer (NK) and CD8 T cells. We will investigate the role of T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) in well- characterized subjects from the Options study of early HIV-1 infection and the SCOPE study of chronic HIV-1 infection, both based at the University of California, San Francisco. In mice, Tim-3 regulates Th1 responses by binding to its cognate ligand, Galectin-9, to promote T-cell aggregation and the death of interferon-gamma- producing Th1 cells. In our preliminary studies, we found Tim-3 receptors on human CD8 T cells and showed that they are markedly upregulated during progressive HIV-1 infection and may also play a role in the innate immune response. We propose three specific aims: Aim 1: To assess the kinetics of Tim-3 expression on NK cells and HIV-1 specific CD8 T cells in primary HIV-1 infection and determine whether Tim-3 expression predicts the viral set point. Aim 2: To determine whether Tim-3 expression on HIV-1-specific CD8 T cells is lower in HIV-1 elite controllers than in untreated subjects with progressive disease and antiretroviral-treated subjects with undetectable viral loads. Aim 3: To identify the mechanism of Tim-3 induction on NK cells and CD8 T cells by HIV-1 infection and determine whether modulation of the Tim-3 pathway in vitro can reverse effector cell dysfunction. A better understanding of mechanisms of NK cell and CD8 T cell dysfunction in HIV-1 infection through the Tim-3 pathway could lead to new therapeutic modalities to help reverse this immune deficiency. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to investigate how the immune system in HIV-1 fails to eliminate virus, and in particular how NK cells and CD8 T cells, dysfunction in HIV-1 infected patients. We will characterize a novel pathway that leads to these ineffective innate and adaptive immune functions through the study of diverse groups of HIV-1 infected persons, and determine the mechanisms regulating this pathway with the ultimate aim of developing better treatments for HIV-1 infection